Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:7][O:8][CH2:9][Cl:10]>C(OC)(=O)C>[Cl-:10].[CH3:7][O:8][CH2:9][N+:2]1([CH3:1])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CN1CCCC1
Reactant: COCCl
Solvent: COC(C)=O
Product: COC[N+]1(C)CCCC1
Product: [Cl-]
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A 30.0 g quantity of N-methylpyrrolidine (reagent, product of Tokyo Kasei Co., Ltd.) was dissolved in 120 g of methyl acetate, followed by replacement with nitrogen. A 31.2 g quantity of chloromethyl methyl ether (reagent, product of Tokyo Kasei Co., Ltd.) was added dropwise to the solution at 5° C. over a period of 1 hour. The mixture was stirred at 5° C. for 1 hour, the temperature was slowly raised, and the mixture was stirred at room temperature for 10 hours to complete the reaction. The reaction mixture was filtered, and the solid product was washed with 150 g of methyl acetate and 150 g of acetone. The washed product was dried in a vacuum, giving 53.7 g of N-methoxymethyl-N-methylpyrrolidinium chloride. To the chloride salt (53.7 g) obtained was added 71.2 g of 42% aqueous solution of HBF4 to dissolve the salt. Nitrogen was bubbled through the solution at 130° C. to remove water, hydrogen chloride and excessive HBF4. To the solution was added 70 ml of methanol, and nitrogen was bubbled through the mixture at 130° C. to further remove water, hydrogen chloride and excessive HBF4 and obtain 68.2 g of the desired electrolyte, i.e., N-methoxymethyl-N-methylpyrrolidinium tetrafluoroborate (water: 30 ppm, methylpyrrolidine tetrafluoroborate: 4000 ppm). To 68.2 g of the electrolyte were added 2.0 g of barium chloride and 70 ml of methanol within a glove box having an argon atmosphere with a dew point of −60° C. Nitrogen was bubbled through the mixture at 130° C. to remove the methanol, followed by filtration with a membrane filter and analysis.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8]([CH3:27])[C:9]([CH2:18][C:19](=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:5]2=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[N:6]2[N:7]=[C:8]([CH3:27])[C:9]([CH2:18][CH:19]([OH:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)Cc1c(C)nn2c(Cl)ccc2c1-c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CC(O)Cc1c(C)nn2c(Cl)ccc2c1-c1ccc(F)cc1
Reaction time: 1 h
Yield: 59.1 %

Procedure:
To a solution of ethyl 4-[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-3-oxo-butanoate (160 mg) in methanol (5 ml) was added sodium borohydride (23.4 mg) at 0° C. and the mixture was stirred at the same temperature for 1 hour. The mixture was partitioned between 1N hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was purified by preparative thin-layer chromatograpy eluting with a mixture of ethyl acetate and hexane (1:3) and triturated with ethyl acetate to give ethyl 4-[7-chloro-4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]-3-hydroxybutanoate (95 mg) as an yellow powder.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C:10]([N:12]1[CH2:17][CH2:16][C:15]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:11])=O)(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[NH2:8][C@H:9]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1)[C:10]([N:12]1[CH2:17][CH2:16][C:15]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:11]
Reactant: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(C2CCCCC2)CCN(C(=O)[C@H](N)Cc2ccc(OC)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To 10 g (19.4 mmol) of ethyl 1-[(R)-2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)-propionyl]-4-cyclohexylpiperidine-4-carboxylate (cf. preparation 4-3) in 80 ml of dichloromethane are added 20 ml of trifluoroacetic acid. The reaction medium is stirred for 2 hours at room temperature. The solvents are evaporated off and diethyl ether is added in the presence of a few drops of dichloromethane. The precipitate obtained is filtered off and then dried under vacuum at 40° C. 8 g of ethyl 1-[(R)-2-amino-3-(4-methoxyphenyl)propionyl]-4-cyclohexylpiperidine-4-carboxylate trifluoroacetate in the form of a white powder are obtained in a yield of 78%.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N+:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([O-])=O>[Cu]>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][CH:2]=[C:3]([N:21]([C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=3)[CH:13]=[CH:12][CH:11]=2)[C:24]2[CH:29]=[CH:28][C:27]([C:27]3[CH:28]=[CH:29][C:24]([N:21]([C:10]4[CH:9]=[C:8]([C:5]5[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=5)[CH:13]=[CH:12][CH:11]=4)[C:3]4[CH:4]=[C:5]([C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)[CH:6]=[CH:7][CH:2]=4)=[CH:25][CH:26]=3)=[CH:26][CH:25]=2)[CH:4]=1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(-c2cccc(N(c3ccc(-c4ccc(N(c5cccc(-c6ccccc6)c5)c5cccc(-c6ccccc6)c5)cc4)cc3)c3cccc(-c4ccccc4)c3)c2)cc1
Yield: 55.7 %

Procedure:
A 500-ml reactor was charged with 44.5 g (0.139 mol) of di(3-biphenyl)amine, 27.6 g (0.0680 mol) of 4,4'-diiodobiphenyl, 34.3 g (0.249 mol) of potassium carbonate, 2.3 g of copper powder, and 180 ml of nitrobenzene. In an argon stream, the contents were heated under reflux for 24 hours. At the end of reaction, the insoluble was removed by filtration and the filtrate was distilled of the solvent. The still residue was purified through a silica gel column with a 3/1 mixture of n-hexane and toluene, obtaining 30 g of N,N,N',N'-tetra(3-biphenylyl)benzidine of primary purity grade (yield 55.7%). It was further purified by recrystallization from toluene, obtaining 6.0 g of a 99.58% pure fraction and 5.0 g of a 99.23% pure fraction (combined yield 20.496). Further purification by sublimation yielded 8.0 g of a 99.99% pure product.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:9])[CH:7]=1.Cl[C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21]>>[Cl:1][C:2]1[C:3](=[O:18])[N:4]([C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21])[C:5](=[O:17])[N:6]([C:8](=[O:9])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:7]=1
Reactant: CC(C)COC(=O)Cl
Reactant: CCCCCCNC(=O)n1cc(Cl)c(=O)[nH]c1=O
Product: CCCCCCNC(=O)n1cc(Cl)c(=O)n(C(=O)OCC(C)C)c1=O
Yield: 29 %

Procedure:
The title compound was obtained according to the procedure described for the synthesis of Example 24, starting from 5-chloro-N-hexyl-2,4-dioxo-pyrimidine-1-carboxamide (Example 3) (0.119 g, 0.431 mmol); 2.4 equivalents of isobutyl chloroformate were used herein. The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 85:15) to afford the title compound (0.047 g, 29%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 0.89 (t, J=6.8 Hz, 3H), 1.01 (d, J=6.7 Hz, 6H), 1.28-1.38 (m, 6H), 1.57-1.64 (m, 2H), 2.11 (h, J=6.7 Hz, 1H), 3.39 (td, J=7.1, 5.5, 2H), 4.26 (d, J=6.6, 2H), 8.62 (s, 1H), 8.80 (t, J=4.9 Hz, 1H). 13C NMR (101 MHz, CDCl3): δ 14.12, 18.89 (2C), 22.63, 26.58, 27.81, 29.19, 31.48, 41.77, 76.77, 111.14, 135.14, 148.40, 148.58, 149.20, 156.04. MS (ESI) m/z: 391 [M-NH4]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[CH2:22][C@@H:21]([CH2:23][C:24]([O:26]CC)=[O:25])[C:20]4[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=4[CH2:18][C:17]=3[CH:33]=2)[CH:3]=1.CC1C=CN=C(NCCCOC2C=CC3C[C@@H](CC(OCC)=O)C4C=CC=CC=4CC=3C=2)C=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]3[CH2:22][C@@H:21]([CH2:23][C:24]([OH:26])=[O:25])[C:20]4[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=4[CH2:18][C:17]=3[CH:33]=2)[CH:3]=1
Reactant: CCOC(=O)C[C@@H]1Cc2ccc(OCCCNc3cc(Cl)ccn3)cc2Cc2ccccc21
Agent: CCOC(=O)C[C@@H]1Cc2ccc(OCCCNc3cc(C)ccn3)cc2Cc2ccccc21
Product: O=C(O)C[C@@H]1Cc2ccc(OCCCNc3cc(Cl)ccn3)cc2Cc2ccccc21

Procedure:
According to the procedure of Example 13 (c), except substituting ethyl (S)-10,11-dihydro-3-[3-(4-chloropyridin-2-ylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate for the ethyl (S)-10,11-dihydro-3-[3-(4-methylpyridin-2-ylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate, the title compound was obtained as off-white powder: MS (ES) 437.2 (M+H)+. Anal. Calcd for C25H25N2O3.1.0 HCl: C, 63.43;. H, 5.54; N, 5.92. Found: C, 63.11; H, 5.82; N, 5.62.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:11]([C:12]#CC(C)=C)=[CH:10][N:9]([CH2:17][C:18]3[C:23]([CH3:24])=[C:22]([O:25][CH3:26])[C:21]([CH3:27])=[CH:20][N:19]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:49]C)C=C4)N(CC2)C1.[CH3:86][C:87]([OH:90])([CH3:89])[CH3:88].O>>[NH2:8][C:6]1[N:7]=[C:2]([Cl:1])[C:3]2[C:11]([C:12]#[C:86][C@:87]([CH3:89])([OH:90])[CH2:88][OH:49])=[CH:10][N:9]([CH2:17][C:18]3[C:23]([CH3:24])=[C:22]([O:25][CH3:26])[C:21]([CH3:27])=[CH:20][N:19]=3)[C:4]=2[N:5]=1
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: CC(C)(C)O
Reactant: C=C(C)C#Cc1cn(Cc2ncc(C)c(OC)c2C)c2nc(N)nc(Cl)c12
Solvent: O
Product: COc1c(C)cnc(Cn2cc(C#C[C@](C)(O)CO)c3c(Cl)nc(N)nc32)c1C

Procedure:
Treatment of 4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-5-(3-methylbut-3-en-1-ynyl)-7H-pyrrolo[2,3-d]pyrimidin-2-amine (see example 51) (263 mg) with AD-mix-α (Aldrich, 1.41 g) in t-BuOH:water 1:1: (7 mL) at rt for 3 days, followed by quench (NaHSO3, 1.6 g), work-up, and preparative HPLC gave the title compound (69 mg), as a solid. HPLC Rt=4.36 min
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][S:17]([C:20]([F:23])([F:22])[F:21])(=[O:19])=[O:18])[N:5]2[CH:24]=1.[CH2:25]=O>C(O)(=O)C>[CH3:1][C:2]1[N:3]=[C:4]2[N:5]3[C:6]([CH2:10][N:11]([CH2:12][CH2:13][CH2:14][CH2:15][NH:16][S:17]([C:20]([F:21])([F:22])[F:23])(=[O:19])=[O:18])[CH2:25][C:24]=13)=[CH:7][CH:8]=[CH:9]2
Reactant: Cc1cn2c(CNCCCCNS(=O)(=O)C(F)(F)F)cccc2n1
Reactant: C=O
Solvent: CC(=O)O
Product: Cc1nc2cccc3n2c1CN(CCCCNS(=O)(=O)C(F)(F)F)C3
Temperature: 100 °C
Yield: 72 %

Procedure:
In 6 ml of acetic acid was dissolved 2.02 g (5.54 mmol) of 2-methyl-5-[N-[4-(trifluoromethanesulfonamido) butan-1-yl]aminomethyl]imidazo[1,2-a]pyridine. To the solution was added 6.2 ml (83.15 mmol) of a 37% aqueous solution of formalin, and the mixture was heated for 30 minutes at 100° C. After completion of the reaction, the solvent was distilled off under reduced pressure. The residue was dissolved in 100 ml of a saturated aqueous solution of potassium carbonate. This solution was neutralized by the addition of 1N HCl under ice-cooling, which was extracted twice with 100 ml of chloroform. The extract was dried over magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was purified by silica-gel column chromatography (eluent: chloroform/methanol=20:1) to afford 1.45 g of the desired compound (72.0%, colorless liquid).
Reaction SMILES: [CH2:1]([C:5]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:8][CH2:7][CH:6]1[OH:10])[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:1]([C:5]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:8][CH2:7][CH:6]1[O:10][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCC1(C(=O)OCC)CCCC1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCC1(C(=O)OCC)CCCC1OC(=O)c1ccccc1
Reaction time: 12 h
Yield: 93.7 %

Procedure:
10.7 grams of ethyl 1-n-butyl-2-hydroxy-cyclopentane carboxylate obtained in Example 16 were diluted with 60 ml of methylene chloride. At room temperature and with magnetic stirring, 6.108 ml of pyridine was slowly added, then 8.876 ml of benzoyl chloride was dropwise added. Upon the completion of the addition, the reaction was continued for 12 hours. Then the procedure as described in Example 23 was followed, to give 19.06 g of brown liquid. The brown liquid was purified through column chromatography to give a liquid with a purity, measured by GC, of 96.03%. Yield: 93.7%. MS: 318(M+), 273(M+—OCH2CH3), 261(M+−CH2CH2CH2CH3), 245(M+—CO2CH2CH3), 213, 197(M+—C6H5CO2), 105(base), 77.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1.[C:11](=O)([O-])[O-].[K+].[K+].CI.O>CN(C)C=O>[F:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[CH:9]=[CH:10][C:5]2=[CH:4][CH:3]=1
Reactant: Fc1ccc2cc[nH]c2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc2ccc(F)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a solution of 6-fluoro-1H-pyrrolo[2,3-b]pyridine (250 g, 1.84 mol) in dimethylformamide (2.50 L) is added potassium carbonate (507.6 g; 3.67 mol), followed by methyl iodide (171.6 mL, 2.75 mol). The reaction is stirred at room temperature overnight. The reaction mixture is poured into water (3000 mL) and extracted with Et2O (3×1500 mL). The organic extracts are combined and washed with water (4×1000 mL), then brine, and dried over Na2SO4. The solvent is evaporated to give a light brown oil which, on standing, gives clear colorless crystals, with a little mobile liquid on top of the crystals. The liquid is decanted off and discarded to leave the product as a crystalline solid (257.3 g, 1.71 moles). 1H-NMR (400 MHz, CDCl3): δ 7.93 (t, 1H), 7.11 (d, 1H), 6.69 (d, 1H), 6.46 (d, 1H), 3.83 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([OH:16])=O)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:7]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[CH2:46]([NH2:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>ClCCl.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:14]([NH:53][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:16])=[N:4][C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][N:7]=1
Reactant: NCc1ccccc1
Reactant: Nc1ncc(-c2ccccc2)nc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: Nc1ncc(-c2ccccc2)nc1C(=O)NCc1ccccc1
Reaction time: 8 h
Yield: 63.6 %

Procedure:
To a solution of 3-amino-6-phenylpyrazine carboxylic acid (0.10 g, 0.47 mmol) in dichloromethane (3 mL) were added 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI, 0.11 g, 0.56 mmol), 1-hydroxybenzotriazole (HOBT, 75 mg, 0.56 mmol), and N-methylmorpholine (NMM, 56 mg, 0.56 mmol) at room temperature. The reaction was stirred for 15 min before benzylamine (0.56 mmol) was added. The reaction mixture was allowed to stir overnight. The reaction was diluted with ethyl acetate (200 mL) and washed with water (50 mL), saturated aqueous sodium bicarbonate (40 mL) and aqueous hydrochloric acid (30 mL), and saturated aqueous sodium chloride (25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated at reduced pressure to afford product (91 mg, 67% yield) as light yellow solid: 1H NMR (400 MHz, CDCl3): δ 8.62 (s, 1H), 8.38 (br s, 1H), 7.84 (dd, 2H), 7.45 (m, 2H), 7.38 (m, 6H), 4.70 (d, 2H); MS (EI) for C18H16N4O: 305 (MH+).
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.Cl[CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.[K+].[Br-]>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Reactant: ClCc1cccc2ccccc12
Agent: [Br-]
Agent: [K+]
Product: O=C1C(CCO)Oc2ccccc2N1Cc1cccc2ccccc12

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Methods F and G, alkylating with 1-chloromethylnaphthalene, in 42% overall yield. The crude product was crystallized from ether/EtOAc/hexane to afford a white solid, mp 100°-104° C.; IR (KBr) 3435, 2896, 1668, 1504, 1414, 1253, 1132, 1068, 768, 758 cm-1 ; 1H NMR (CDCl3) δ 1.92 (br s, 1H Plus HDO), 2.26-2.44 (m, 2H), 3.96 (t, J=5.6 Hz, 2H), 4.94 (dd, J=7.5, 5.6 Hz, 1H), 5.62 (ABq, JAB =16.9 Hz, 2H), 6.72 (dd, J=8.0, 1.1 Hz, 1H), 6.84 (td, J=8.1, 1.5 Hz, 1H), 6.96-7.11 (m, 3H), 7.36 (t, J=7.4 Hz, 1H), 7.54-7.64 (m, 2H), 7.78 (d, J=8.2 Hz, 1H), 7.92 (d, J=7.8 Hz, 1H), 8.04 (d, J=8.1 Hz, 1H); MH+ at m/z=334; Anal. Calc'd for C21H19NO3 : C, 75.66; H, 5.74; N, 4.20. Found: C, 75.56; H, 5.80; N, 4.14.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]C(O)=O)[S:2]1.Cl.[CH3:15][O:16][C:17](=[O:20])[CH2:18][NH2:19].C[N:22](C)[CH:23]=[O:24]>C1(C)C=CC=CC=1.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>[S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:22][C:23](=[O:24])[NH:19][CH2:18][C:17]([O:16][CH3:15])=[O:20])[S:2]1
Reactant: O=C(O)CCCCCC1CCSS1
Reactant: CN(C)C=O
Reactant: COC(=O)CN
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)CNC(=O)NCCCCCC1CCSS1

Procedure:
The reaction was carried out as described in Example 46, but using 10 ml of a solution of 1.5 mmol of 6-(1,2-dithiolan-3-yl)hexanoic acid (prepared as described in Example 104) in toluene, 6 ml of anhydrous toluene, 0.42 ml of triethylamine, 0.39 ml of diphenylphosphoryl azide, 6 ml of anhydrous dimethylformamide and 254 mg of glycine methyl ester hydrochloride. The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 1:4 and 3:2 by volume mixtures of ethyl acetate and hexane as the eluent. The solvent was removed from the eluate by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilised, to obtain 16 mg of the title compound as yellow crystals having an Rf value of 0.62 (silica gel thin layer chromatography; using a 2:3 by volume mixture of ethyl acetate and hexane as developing solvent).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[Cl-].[CH3:12][O:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+]>O1CCCC1>[CH3:9][O:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[CH:1]=[CH:12][O:13][CH3:14]
Reactant: COc1cccc(C=O)c1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
Ninety grams of m-anisaldehyde, 250 g of (methoxymethyl)triphenylphosphonium chloride and 800 ml of tetrahydrofuran were mixed, and then 82.5 g of potassium tert-butoxide was added to this mixed suspension under ice-cooling, and the solution was stirred for 2 hours at room temperature. The reaction solution was poured in ice water, and after distilling out the THF, the mixture was extracted with ethyl acetate. The extract solution was washed with sodium bicarbonate aqueous solution and dried. The extract solution was concentrated to obtain a residue to which hexane was then added, and the resulting precipitate was filtered out. The filtrate was then concentrated, and the residue was subjected to silica gel column chromatography. Elution was then performed with a mixed solvent of hexane:ethyl acetate=20:1, to obtain 90 g of methyl (3-methoxystyryl) ether.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][C:4](=[O:6])[CH3:5].[CH3:8][O:9][C:10]1[CH:20]=[CH:19][C:13]([CH2:14][NH:15][C:16]([NH2:18])=[S:17])=[CH:12][CH:11]=1.N1C=CC=CC=1>CO>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][NH:15][C:16]2[S:17][C:3]([C:4](=[O:6])[CH3:5])=[C:2]([CH3:1])[N:18]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(CNC(N)=S)cc1
Reactant: CC(=O)CC(C)=O
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc(CNc2nc(C)c(C(C)=O)s2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred suspension of 3-chloro, 2,4-pentanedione (1.0 g, 7.43 mmol) and 1-(4-methoxy benzyl)-2-thiourea (1.46 g, 7.43 mmol) in methanol (10 ml) is treated with pyridine (0.6 ml). The reaction mixture is stirred at room temperature for 2 hours and then the solvent is removed in vacuo. The crude residue is triturated with ether to yield the titled compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:25]=[CH:24][C:9]([CH2:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:13]([CH2:22][CH3:23])[N:12]=2)=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH:26]([C@@H:28]1[C@@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=2)[CH2:31][N:30]([C@H:40]([CH:51]2[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]2)[C:41]([O:43]CC2C=CC=CC=2)=[O:42])[CH2:29]1)=O>>[NH4+:12].[C:1]([O:5][C:6]1[CH:25]=[CH:24][C:9]([CH2:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:21][CH2:20][N:19]([CH2:26][C@@H:28]4[C@@H:32]([C:33]5[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=5)[CH2:31][N:30]([C@H:40]([CH:51]5[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]5)[C:41]([O-:43])=[O:42])[CH2:29]4)[CH2:18][CH2:17]3)[N:13]([CH2:22][CH3:23])[N:12]=2)=[CH:8][CH:7]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C[C@H]1CN([C@@H](C(=O)OCc2ccccc2)C2CCCCC2)C[C@@H]1c1cccc(F)c1
Reactant: CCn1nc(Cc2ccc(OC(C)(C)C)cc2)cc1C1CCNCC1
Product: CCn1nc(Cc2ccc(OC(C)(C)C)cc2)cc1C1CCN(C[C@H]2CN([C@@H](C(=O)[O-])C3CCCCC3)C[C@@H]2c2cccc(F)c2)CC1
Product: [NH4+]

Procedure:
The title compound was prepared using procedures described in Example 570 Steps D and E using 4-(3-(4-t-butoxybenzyl)-1-ethyl-(1H-pyrazol-5-yl))piperidine, from Example 570 Step C and Aldehyde 6. ESI-MS 659.4 (M+H), HPLC A: 4.10 min.
Reaction SMILES: C(O)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7][CH2:6]1.[C:18]([C:20]1[CH:30]=[CH:29][C:23]([C:24]([N:26]=[C:27]=[O:28])=[O:25])=[CH:22][CH:21]=1)#[N:19].C(#N)C>C(N(CC)CC)C>[C:18]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([NH:26][C:27]([N:5]2[CH2:6][CH2:7][CH:8]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:10]2)=[O:28])=[O:25])=[CH:29][CH:30]=1)#[N:19]
Reactant: CCOC(=O)COC1CCNCC1
Reactant: N#Cc1ccc(C(=O)N=C=O)cc1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOC(=O)COC1CCN(C(=O)NC(=O)c2ccc(C#N)cc2)CC1
Yield: 54 %

Procedure:
In a similar manner to Example 1, starting material step (a), the product from step (b) (1.7 g), 4-cyanobenzoyl isocyanate (1.1 g), acetonitrile (100 ml total) and triethylamine (2.1 ml) were stirred at ambient temperature overnight. The mixture was evaporated and the residue was purified by column chromatography on silica eluting with 5% ethanol/dichloromethane to give ethyl N-[N-(4-cyanobenzoyl)carbamoyl]piperidin-4-yloxyacetate (1.24 g) as a pale yellow oil: NMR Spectrum (DMSO-d6) 1.21 (3H, t), 1.50 (2H, m), 1.87 (2H, m), 3.20 (2H, m), 3.67 (3H, m), 4.12 (2H, q), 4.15 (2H, s), 7.97 (4H, s), 10.40 (1H, br s); Mass Spectrum m/Z 360 (M+H)+.